title: A key role for Plasmodium subtilisin-like SUB1 protease in egress of malaria parasites from host hepatocytes.
abstract: In their mammalian host, Plasmodium parasites have two obligatory intracellular development phases, first in hepatocytes and subsequently in erythrocytes. Both involve an orchestrated process of invasion into and egress from host cells. The Plasmodium SUB1 protease plays a dual role at the blood stage by enabling egress of the progeny merozoites from the infected erythrocyte and priming merozoites for subsequent erythrocyte invasion. Here, using conditional mutagenesis in P. berghei, we show that SUB1 plays an essential role at the hepatic stage. Stage-specific sub1 invalidation during prehepatocytic development showed that SUB1-deficient parasites failed to rupture the parasitophorous vacuole membrane and to egress from hepatocytes. Furthermore, mechanically released parasites were not adequately primed and failed to establish a blood stage infection in vivo. The critical involvement of SUB1 in both pre-erythrocytic and erythrocytic developmental phases qualifies SUB1 as an attractive multistage target for prophylactic and therapeutic anti-Plasmodium intervention strategies.
authors.affiliation: From the Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Département de Parasitologie et de Mycologie, F-75015 Paris, France.
authors.forename: Lina
authors.initials: L
authors.lastname: Tawk
authors.forename: Céline
authors.initials: C
authors.lastname: Lacroix
authors.forename: Pascale
authors.initials: P
authors.lastname: Gueirard
authors.forename: Robyn
authors.initials: R
authors.lastname: Kent
authors.forename: Olivier
authors.initials: O
authors.lastname: Gorgette
authors.forename: Sabine
authors.initials: S
authors.lastname: Thiberge
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.forename: Robert
authors.initials: R
authors.lastname: Ménard
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Barale
mesh_terms: D000818:Animals; D022781:Hepatocytes / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology; D008288:Malaria / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D016296:Mutagenesis; D010962:Plasmodium berghei / Q000201:enzymology* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D013381:Subtilisins / Q000235:genetics / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology
chemical_list: D015800:Protozoan Proteins; D013381:Subtilisins
keywords: Conditional Mutagenesis; Egress; Hepatocyte; Malaria; Molecular Genetics; Plasmodium; Protease; Subtilisin